Hollow microspheres with controlled fragility for medical use

Abstract

A composition for ultrasonic imaging is described having a microbubble population of controlled fragility. The microbubbles comprise an outer shell and a hollow core. The ratio of shell thickness to microbubble diameter is substantially similar across the population of microbubbles. A method of using such composition for imaging a fluid filled cavity, vessel or tissue is described.

What is claimed is:  
     
       1. A method of echographic imaging using a microbubble contrast agent in a region of interest within a fluid-filled cavity, vessel, or fluid perfused tissue comprising the steps of: 
       a. introducing a microbubble contrast agent consisting of a microbubble population having a constant wall thickness to diameter ratio that is characterized by a threshold intensity of ultrasonic power of microbubble rupture that is within the power range useful for diagnostic imaging into said region of interest,  
       b. applying an ultrasonic signal to said region of interest at an applied power intensity greater than said threshold intensity.  
     
     
       2. A method according to  claim 1  comprising the further steps of ultrasonically recording signal generated by destruction of the microbubble. 
     
     
       3. A method according to  claim 1  comprising the further steps of reducing the applied power intensity to less than said threshold intensity, then ultrasonically recording the reflow of said microbubble agent into the region of interest. 
     
     
       4. A method according to  claim 1 , wherein said microbubble population is comprised of microbubbles having diameters within the range of 1 to 10 microns. 
     
     
       5. A method according to  claim 1 , wherein said microbubble population comprises hollow microbubbles having a shell consisting essentially of a single layer. 
     
     
       6. A method according to  claim 5 , wherein said microbubbles comprise a biodegradable polymer. 
     
     
       7. A method according to  claim 6 , wherein said polymer is a biocompatible amphiphilic material. 
     
     
       8. A method according to  claim 1 , wherein said microbubble population comprises microbubbles having an outer shell comprising an outer layer of biologically compatible amphiphilic material and an inner layer of a biodegradable polymer. 
     
     
       9. A method according to  claim 7  or  8 , wherein said amphiphilic material comprises a protein. 
     
     
       10. A method according to  claim 9  wherein said protein comprises collagen, gelatin, albumin, or globulin. 
     
     
       11. A method according to  claim 6  or  8 , wherein said biodegradable polymer comprises polycaprolactone, polylactide, polyglycolide, polyhydroxyvalerate, polyhydroxybutyrate, or copolymers or mixtures thereof. 
     
     
       12. A method according to  claim 1  wherein said region of interest is the heart. 
     
     
       13. A method according to  claim 1  wherein said region of interest is the kidney. 
     
     
       14. A method according to  claim 1  wherein said region of interest is the liver. 
     
     
       15. A method according to  claim 1  wherein said threshold intensity of ultrasonic power sufficient to induce rupture of said microbubbles is at a Mechanical Index of between 0.1 and 2.6. 
     
     
       16. An ultrasound imaging contrast agent comprising a microbubble population having a controlled fragility wherein each microbubble of said population comprises an outer shell and a hollow core, said outer shell having a wall thickness that forms a ratio with the microbubble diameter that is substantially the same as the wall thickness to diameter ratio of all other microbubbles in the population. 
     
     
       17. A contrast agent according to  claim 16 , wherein said microbubble population comprises microbubbles having diameters within the range of 1 to 10 microns. 
     
     
       18. A contrast agent according to  claim 16 , wherein said microbubble population comprises hollow microparticles having a shell consisting essentially of a single layer. 
     
     
       19. A contrast agent according to  claim 18 , wherein said microbubbles comprise a biodegradable polymer. 
     
     
       20. A contrast agent according to  claim 19 , wherein said polymer is a biocompatible amphiphilic material. 
     
     
       21. A contrast agent according to  claim 16 , wherein said microbubble population comprises microbubbles having an outer shell comprising an outer layer of biologically compatible amphiphilic material and an inner layer of a biodegradable polymer. 
     
     
       22. A contrast agent according to  claim 20  or  21 , wherein said amphiphilic material comprises a protein. 
     
     
       23. A contrast agent according to  claim 22  wherein said protein comprises collagen, gelatin, albumin, or globulin. 
     
     
       24. A contrast agent according to  claim 19  or  21 , wherein said biodegradable polymer comprises polycaprolactone, polylactide, polyglycolide, polyhydroxyvalerate, polyhydroxybutyrate, or copolymers or mixtures thereof. 
     
     
       25. A contrast agent according to  claim 16  wherein said ultrasound imaging contrast agent is imaged by means of ultrasound B-mode imaging methods. 
     
     
       26. A contrast agent according to  claim 16  wherein said ultrasound imaging contrast agent is imaged by means of ultrasound doppler methods. 
     
     
       27. A contrast agent according to  claim 16  wherein said ultrasound imaging contrast agent is imaged by means of ultrasound pulsed inversion methods.